Gluten Cross-Reactivity UPDATE: How your body can still think you’re eating gluten even after giving it up.

March 13, 2013 in Categories: , , , , , by

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The Paleo Approach by Sarah BallantyneIn my research for The Paleo Approach, I feel that it is important to provide scientific references for every single statement I make.  This has me doing a great deal of fact checking, scouring the medical literature to verify information often gleaned from other paleo authors and bloggers.  Most of the time what I find out just helps reinforce concepts, filling in blanks, and typically making a strong case for my assertions.  But, every once in a while, I find information that makes me completely reevaluate a concept and sometimes even an aspect of the autoimmune protocol.

The update for this blog post comes from my further examination into the science behind gluten cross-reactivity.  While there are plenty of papers confirming how cross-reactive antibodies can be formed, I could not find any published studies confirming the results from Cyrex Labs (and my motto with the paper is if I can’t cite it, I don’t say it).  I contacted the company to request further information (I was particularly interested in the reported cross-reactivity to tapioca as I was trying to decide whether or not tapioca starch and/or pearls should be included in The Paleo Approach).  Cyrex labs responded quickly and informatively and my level of esteem for that company (which was high to begin with) elevated another couple of notches.  While they were unwilling to share proprietary data with me, they were able to point me to a recent publication that evaluated gluten cross-reactivity and share a summary of their proprietary findings (the paper did not show up on my PubMed searches).  As I devoured the paper (figuratively, not literally), I realized that an update to this post was required.  This is not an excerpt from The Paleo Approach but it is a direct result of my research for the book and much of the information that follows is still presented in it.

For those 20% of us with celiac disease or gluten-intolerance/sensitivity (whether diagnosed or not), it is critical to understand the concept of gluten cross-reactivity. Essentially, when your body creates antibodies against gluten, those same antibodies also recognize proteins in other foods. When you eat those foods, even though they don’t contain gluten, your body reacts as though they do. You can do a fantastic job of remaining completely gluten-free but still suffer all of the symptoms of gluten consumption—because your body still thinks you are eating gluten. This is a very important piece of information that I was missing until recently.

Proteins are made of long chains of amino acids (small proteins may only be 50 amino acids long whereas large proteins may be 2000 amino acids long) and it is the specific sequence of these amino acids that determines what kind of protein is formed. These amino acid chains are folded, kinked and buckled in extremely complex ways, which gives a protein its ‘structure’. This folding/structure is integral to the function of the protein.

An antibody is a Y shaped protein produced by immune cells in your body. Each tip of the Y contains the region of the antibody (called the paratope) that can bind to a specific sequence of amino acids (called the epitope) that are a part of the protein that the antibody recognizes/binds to (called the antigen). The classic analogy is that the antibody is like a lock and a 15-20 amino acid section of a protein/antigen is the key. There are 5 classes (or isotypes) of antibodies, each with distinctive functions in the body. The IgE class of antibodies are responsible for allergic reactions; for example, when someone goes into anaphylaxis after eating shellfish. The two classes IgG and IgA are critical for protecting us from invading pathogens but are also responsible for food sensitivities/intolerances. Both IgA and IgG antibodies are secreted by immune cells into the circulation, lymph, various fluids of the body (like saliva!) and tissues themselves. And both IgG and IgA antibodies are found in high concentrations in the tissues and fluids surrounding the gut (this is part of why the gut is considered our primary defense against infection).

The formation of antibodies against an antigen (whether this is an invading pathogen or a food) is an extremely complex process. When antibodies are being formed against a protein, the antibodies recognize specific (and short) sequences of amino acids in that protein. Depending on how the antigenic protein is folded, certain amino acid sequences in that protein are more likely to be the target of new antibody formation than others, simply because of the location of that sequence in the structure of the protein. Certain sequences of amino acids are more antigenic than others as well (i.e., more likely to stimulate antibody formation). This is also part of why certain foods have a higher potential to cause allergies and sensitivities.

Understanding that antibodies recognize short sequences of amino acids and not an entire protein is key to understanding the concept of cross-reactivity (and molecular mimicry, but that’s a topic for another post). It also is the reason why many different antibodies can be formed against one protein (this redundancy is important for protecting us from pathogens). Many different antibodies can also be formed against one pathogen or, more relevant to this discussion, one specific food.

So what happens in cross-reactivity? In this case the amino acid sequence that an antibody recognizes is also present in another protein from another food (in the case of molecular mimicry, that sequence is also present is a protein in the human body). There are only 20 different amino acids, so while there are millions of possible ways to link various amount of each amino acid together to form a protein, there are certain amino acid sequences that do tend to repeat in biology.

The take home message: depending on exactly what antibody or antibodies your body forms against gluten, it/they may or may not cross-react with other foods. So, not only are you sensitive to gluten, but your body now recognizes non-gluten containing foods as one and the same. Who needs to worry about this? Any of the estimated 20% of people who are gluten intolerant or have celiac disease, i.e., have formed antibodies against gluten.

A recent study evaluated the potential cross-reactivity of 24 food antigens.  These included:

  • Rye
  • Barley
  • Spelt
  • Polish Wheat
  • Oats (2 different cultivars)
  • Buckwheat
  • Sorghum
  • Millet
  • Amaranth
  • Quinoa
  • Corn
  • Rice
  • Potato
  • Hemp
  • Teff
  • Soy
  • Milk (Alpha-Casein, Beta-Casein, Casomorphin, Butyrophilin, Whey Protein and whole milk)
  • Chocolate
  • Yeast
  • Coffee (instant, latte, espresso, imported)
  • Sesame
  • Tapioca (a.k.a. cassava or yucca)
  • Eggs

They did not find cross-reactivity with all of these foods (as is implied by the Cyrex Labs gluten cross-reactivity blood test, a.k.a. Array 4).  But, they did find that their anti-gliadin antibodies (antibodies that recognize the protein fraction of gluten) did cross-react with all dairy including whole milk and isolated dairy proteins (casein, casomorphin, butyrophilin, and whey)—this may explain the high frequency of dairy sensitivities in celiac patients—oats, brewer/baker’s yeast, instant coffee (but not fresh coffee), milk chocolate (attributable to the dairy proteins in chocolate), sorghum, millet, corn, rice and potato.

While not all people with gluten sensitivities will also be sensitive to all of these foods, they should be highlighted as high risk for stimulating the immune system.   Just like trace amounts of gluten can cause a reaction in at least those with celiac disease (the threshold for a reaction has not been tested in non-celiac gluten sensitivity), even a small amount of these foods can perpetuate inflammation and immune responses. This is important when you think of the small amounts of corn used in so many foods and even the trace milk proteins that can be found in ghee.

Beyond this gluten contamination is common in the food supply and many grains and flours that are inherently gluten free may still contain gluten once processed.  Commonly contaminated grain products include millet, white rice flour, buckwheat flour, sorghum flour, and soy flour.  As these are commonly used ingredients in commercial gluten-free baked goods, extreme caution should be exercised.

Cyrex Labs offers a simple blood test that is referred to as their gluten ross-reactivity panel, a.k.a. Array 4.  It tests for reactions to the gluten cross-reactors mentioned above as well as the non cross-reactors evaluated in the paper.  Cyrex Labs reported to me that they see positive sensitivities frequently (many as high as 25%) in many of those foods in people with diagnosed gluten sensitivity.  This may reflect that when you have a leaky gut, food intolerances are quite easy to form.

If you have autoimmune disease (which has a very high correlation with gluten-sensitivity), celiac disease, gluten-sensitivity, or are simply not seeing the improvements you were hoping for by following a standard paleo diet, one or all of these foods may be the culprit. You have the choice of either cutting these foods out of your diet and seeing if you improve or get tested to see if your body produces antibodies against these foods.

When I first wrote this blog post, it made so many pieces of the puzzle come together.  I stopped eating chocolate (I had already given up coffee), fermented foods like sauerkraut and kombucha (because of the yeast content), eggs, and tapioca.  Over the months that followed, I was able to definitely discern that I am very sensitive to chocolate (perhaps because it is extremely high in phytic acid, discussed in this post) and eggs (discussed in this post).  I have successfully reintroduced fermented foods and have not been particularly inspired to test my sensitivity to tapioca (I test by eating a bit and seeing if I have a reaction, most typically my reactions are acne, but sometimes trouble sleeping, mood issues, joint aches, or increased itchiness and redness of my lichen planus lesions).  So, will I give coffee a try now?  Maybe, once in a while as a special treat, but removing gluten cross-reactivity from the list of ways coffee is suboptimal, really only removes one potential problem.  Coffee still has effects on cortisol and still correlates with increased inflammation.  Oh well.  Whether I can drink coffee again or not, I am glad to be able to share this updated information with all of you!

A great overview of proteins and antibodies (and source of protein folding image):

A fairly technical review of food IgG-mediated food sensitivities:

Cyrex Labs Array 4:

Image of antibody binding taken from

A. Vojdani and I. Tarash, “Cross-Reaction between Gliadin and Different Food and Tissue Antigens,” Food and Nutrition Sciences, Vol. 4 No. 1, 2013, pp. 20-32.

Thompson T et al. Gluten contamination of grains, seeds, and flours in the United States: a pilot study. J Am Diet Assoc. 2010 Jun;110(6):937-40. doi: 10.1016/j.jada.2010.03.014.


Hi there,

I am 35, have had Hashi’s since I’m 17 (after mono), suspected to have leaky gut, went gluten free and on Paleo for almost a year, and have been referred to the Array-4 test which is how I fell on this page (doing research- so glad I found you!) because I still feel fatigue and much brain fog even after working with my ND to fix digestive issues and yeast in the gut. I will certainly look into the AIP now. I have very low ferritin as it is and some hair loss so I hope that won’t get worse.

But my question is for my 4 year old daughter: how do I avoid her developing leaky gut in the first place? From all the posts I read on this site, it sounds like this condition can be healed and some foods even re-introduced, but how did it happen in the first place? Do we need to reduce gluten x reactive foods for our kids to minimize their odds of having leaky gut? My daughter is such a picky eater and I try to make her eat GF as much as possible but I don’t want to restrict her diet if there is no reason to. I feel helpless sometimes and wonder if I am putting her at risk later (not to mention my stress) by not exposing her to certain foods. How can I tell if she is at risk for leaky gut? She is terrified of blood tests and I wonder if it would be accurate to have the Array-4 done at such a young age?

Thanks so much.

I’m confused in particular as to whether tapioca is a cross reactive substance? I’m also wondering about rice, and what element of that can hinder an autoimmune sufferer (aside from any high blood sugar it may cause)?

Tapioca is not cross-reactive. Rice can be cross-reactive, but you’d have to get Array 4 to know for sure if you react to it that way. I had Array 4 done and I cross-reacted to casein, whey, and potato, as well as to soy (not a cross-reaction, though). The other cross-reactors tested clear for me but, since I hadn’t eaten millet or sorghum in a long time, there’s a chance for false negatives regarding those.

I’m confused since you mention that tapioca was not found to be cross reactive but you removed it. Are you suggesting the entire list above could still have gluten cross reactivity even if not proven by Cyrex testing?

I appreciate your scientific integrity of not saying it if you can’t cite it. There is a lot of nutritional claims on the internet that may or may not be backed by science. If I really want to, I can read your cites myself and evaluate what you are trying to explain in a more accessible way. I also appreciate that you don’t cling to an opinion when new research demonstrates a need to clarify or update your blog. Protein sequences and antibodies make sense. Mythical cavemen do not.

Thanks for the info….. But it’s just one of thousands that tell us what NOT to eat and doesn’t give any hope!! Sure be nice if for once a blogger would actually give helpful advice and give some suggestions as opposed to just leaving people feel stupid and hopeless! Nice!

I did the cyrex crossreactivity this year and it showed positive for 4 items: amaranth, millet, buckwheat, and tapioca. Interestingly enough, coffee did not come up positive, but I don’t tolerate it well. I have history of high evening cortisol/insomnia. I get itchy skin and joint pain in hands and feet from exposure to gluten. Great article! Wondering if I may ever be able to reintroduce these items into diet.

Thank you for taking the time to compose such a well researched article! Hopefully you didn’t address my question in the post, and I just missed it! When you say “yeast” does that include beneficial yeasts, such as s. boulardii? I am assuming it must if that is the reason you eliminated kombucha and fermented foods from your diet. Thanks in advance!

It has been a while since you updated this post. In the months since you began your healing, have you been able reintroduce any of the other cross reactive items on the list?
Do you think I shall ever be able to have dairy again? I have ulcerative colitis.
Thanks for the great blog!!

Raghav, the issue with cross-reactive foods is that the immune system thinks they’re gluten, so those reactions are permanent, as opposed to other food sensitivities that are due to leaky gut and could be reverse over time. If you’ve had Array 4 and you know that you cross-react to dairy, it’s out for good.

Thank you so much for this update! It has answered a lot of ‘why am I still getting sick?’ questions when I was being so careful being gluten/dairy free and then Paleo. There has been a huge improvement with my health since I started AIP, and this gives me a bit more insight into why (we suspect corn, potato and/or rice cross reactivity may be the cause). I’m in Australia and I’m hoping my Dr will be able to order the Array 4 test for me here. Thanks again for all your research!!

Thanks for the informative article. Based on your sensitivities and symptoms, have you looked into histamine intolerance? Chocolate, fermented foods and some of the others that you listed are major offenders for those that are histamine intolerant. And the symptoms you list also line up with that. It might end up being that if you supplement for treating histamine intolerance you will no longer be sensitive to some of the foods you listed…?

Does anyone know if the reverse is true? People who KNOW they are dairy sensitive–is it more likely they are also gluten sensitive? Been wondering about this for a while.

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